Animals, seed plants, and fungi commonly store excessive amounts of energy substrates in the form of intracellular triglyceride (TG) deposits. In mammals, TG are stored in adipose tissue providing the primary source of energy during periods of food deprivation. Whole body energy homeostasis depends on the precisely regulated balance of lipid storage and mobilization. Mobilization of fatty acids from triglyceride stores in adipose tissue critically depends on the activation of lipolytic enzymes, which degrade adipose TG and release non-esterified fatty acids (FA) into the circulation. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Dysregulation of TG-lipolysis in man has been linked to variation in the concentration of circulating FA, an established risk factor for the development of insulin resistance (Bergman, R. N. et al (2001) J Investig Med 49: 119-26; Blaak, E. E. (2003) Proc Nutr Soc 62: 753-60; Boden, G. and G. I. Shulman (2002) Eur J Clin Invest 32(Suppl 3):14-23; Arner, P. (2002) Diabetes Metab Res Rev 18(Suppl 2): S5-9).
During periods of increased energy demand, lipolysis in adipocytes is activated by hormones, such as catecholamines. Hormone interaction with G-protein coupled receptors is followed by increased adenylate cyclase activity, increased cAMP levels, and the activation of cAMP-dependent protein kinase (protein kinase A, PKA) (Collins, S. and R. S. Surwit (2001) Recent Prog Horm Res 56:309-28). PKA then phosphorylates targets with established function in lipolysis including hormone-sensitive lipase (HSL), resulting in the translocation of HSL from the cytoplasm to the lipid droplet where efficient TG hydrolysis occurs (Sztalryd, C. et al (2003) J Cell Biol 161:1093-103).
The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol liposis. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown. ATGL (also named PNPLA 2 (patatin-like phospholipase domain containing protein-2, desnutrin, phospholipase A2δ, and transport-secretion protein)) is highly expressed in adipose tissue and specifically removes the first fatty acid from the TG molecule, generating FFA and DG (Zimmerman, R. et al (2006) Science 306:1383-1386; Wang, S P et al (2001) Obes Res 9:119-128; Villena, J A et al (2004) J Biol Chem 279:47066-47075; Jenkins, C M et al (2004) J Biol Chem 279:48968-48975). An essential role of ATGL in lipolypsis has been demonstrated in studies of ATGL-deficient (ATGL-ko) mice (Haemmerle, G. et al (2006) Science 312:734-737). ATGL-deficient mice accumulated large amounts of lipid in the heart, causing cardiac dysfunction and premature death. The relative contribution of these hydrolases to the lipolytic catabolism of fat has been determined, including in mutant mouse models lacking ATGL or HSL (Schweiger, M. et al (2006) J Biol Chem 281(52):40236-40241). Both HSL and ATGL enzymes contribute to hydrolysis of TG, however, ATGL deficient mice studies indicate that ATGL is rate limiting in the catabolism of cellular fat deposits and plays an important role in energy homeostasis (Haemmerle, G. et al (2006) Science 312(5774):734-737).
Cachexia is loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite in someone who is not actively trying to lose weight. It can be a sign of various underlying disorders; when a patient presents with cachexia, a doctor will generally consider the possibility of cancer, certain infectious diseases (e.g. tuberculosis, AIDS), and some autoimmune disorders, or addiction to drugs such as amphetamines or cocaine, chronic alcoholism and cirrhosis of the liver. Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor (Lainscak M, et al (2007) Curr Opin Support Palliat Care 1(4): 299-305; Bossola M et al (2007) Expert Opin Investig Drugs 16 (8): 1241-53).
Cachexia is often seen in end-stage cancer, and in that context is called “cancer cachexia”. It was also prevalent in HIV patients before the advent of highly active anti-retroviral therapy (HAART) for that condition; now it is seen less frequently in those countries where such treatment is available. In those patients who have Congestive Heart Failure, there is also a cachectic syndrome. Also, a cachexia co-morbidity is seen in patients that have any of the range of illnesses classified as “COPD” (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia can present this condition where it is named vesanic cachexia (from vesania, a Latin term for insanity).
The exact mechanism by which these diseases cause cachexia is poorly understood, but there is postulated a role for inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukins 1 and 6 (IL-1 and IL-6), interferon gamma (IFN-γ), leukemia-inhibitory factor (LAF), as well as ZAG, a 43 kDa soluble glycoprotein as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even with concomitant administration of anti-TNF-α antibody without a cytokine involvement, suggesting that TNF-α may not be responsible for the cachexia and that other factors may be involved (Costelli P et al (1993) J Clin Invest 92:2783-2789; Sherry B A et al (1989) FASEB J 3:1956-1962).
About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. The definitive treatment of cancer cachexia is removal of the causative tumor. Short of achieving this goal, which is often compromised by the patients' inability to tolerate cancer treatments due to their cachexia, various measures have been undertaken to ameliorate cachexia, however with limited success. Various agents have been administered in attempts to retard or halt progressive cachexia in cancer patients. These agents include orexigenic agents (appetite stimulants), corticosteroids, cannabinoids, serotonin antagonists, prokinetic agents, androgens and anabolic agents, anticytokine agents, NSAIDs, and regulators of circadian rhythm.
Despite an increased understanding of ATGL and its role in TG hydrolysis and lipolysis, there is still a need for a fuller and specific understanding of its physiological role and its potential application and/or role in pathological conditions. Cachexia and other relevant wasting syndromes provide a significant and largely unaddressed condition. Improved and specific therapies for these conditions and for the particular modulation of the fat and muscle wasting associated therewith are needed.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.